Reactivation of resolved hepatitis B virus (HBV) infection, which is known as reverse seroconversion (RS), has been reported as a rare complication of allogeneic hematopoietic stem cell transplantation. We retrospectively studied HBV serologic markers in 14 recipients with pretransplant anti-hepatitis B surface antigen antibody (anti-HBs). Progressive decreases in anti-HBs titer were observed in all cases. In 12 cases, anti-HBs titer had decreased to under the protective value. RS occurred in seven cases after disappearance of anti-HBs. Although reseroconversion occurred in five cases, two cases remained in an HBV-carrier status after resolution of hepatitis. In the other five cases, RS did not occur even after disappearance of anti-HBs. The actual risks of anti-HBs disappearance and RS were estimated to be 75.0% and 39.8% at 2 years and 100.0% and 70.0% at 5 years, respectively. In conclusion, RS is a late-onset complication with high frequency that can be predicted by careful monitoring of progressive decrease in anti-HBs titer.

Aggressive resection surgery based on accurate localization with the SASI test was useful for biochemical cure of gastrinoma in patients with MEN 1.

Innate immune cells such as natural killer (NK) cells play a crucial role in antitumor immune responses. NKG2D is a major activating immunoreceptor expressed in not only NK cells but also CD8þ T cells and shows cytotoxicity against tumors by recognizing its ligands major histocompatibility complex class I-related chain A and B (MICA and MICB) on tumor cells. Recently, it has been suggested that NKG2D-mediated cytotoxicity correlates with the expression levels of NKG2D ligands on target cells. In this study, we were able to increase the expression levels of MICA and MICB on leukemic cell lines and patients' leukemic cells by treatment with trichostatin A (TsA), a histone deacetylase (HDAC) inhibitor. Chromatin immunoprecipitation (ChIP) assays revealed that treatment with TsA resulted in increased acetylation of histone H3 and decreased association with HDAC1 at the promoters of MICA and MICB. Intriguingly, upregulation of MICA and MICB by treatment with TsA led to enhancement of the susceptibility of leukemic cells to the cytotoxicity of NKG2D-expressing cells. Our results suggest that regulation of the expression of NKG2D ligands by treatment with chromatin-remodeling drugs may be an attractive strategy for immunotherapy.

Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies who receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the incidence and treatment outcomes of proven and probable IFI in 22 institutions between 2006 and 2008 following the recent European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) consensus criteria. We analyzed 2,821 patients with hematological malignancies, including 597 who had undergone HSCT; these included patients with acute leukemia (n = 697), myelodysplastic syndrome (n = 284), lymphoma (n = 1465), or multiple myeloma (n = 375). IFIs were diagnosed in 38 (1.3%) patients (18 proven and 20 probable), including 20 patients who underwent HSCT and 18 who received chemotherapy alone; these included patients with aspergillosis (n = 23), candidiasis (n = 6), mucormycosis (n = 6), trichosporonosis (n = 2), and geotrichosis (n = 1). The incidence of IFI was 5.4 % in allogeneic HSCT patients, 0.4 % in autologous HSCT patients, and 0.8 % in patients receiving chemotherapy alone. Eighteen patients with aspergillosis were diagnosed with probable pulmonary IFI as determined by computed tomography scan and positive galactomannan assay. Overall, antifungal targeted therapies resulted in successful outcomes in 60.0 % of patients. IFI-attributable mortality rate was higher in HSCT patients than in those receiving chemotherapy alone, but the difference was not statistically significant.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) using post-transplant cyclophosphamide (PTCy) is increasingly performed. We conducted a multicenter phase II study to evaluate the safety and efficacy of PTCy-based HLA-haploidentical peripheral blood stem cell transplantation (PTCy-haploPBSCT) after busulfan-containing reduced-intensity conditioning. Thirty-one patients were enrolled; 61% patients were not in remission and 42% patients had a history of prior allo-SCT. Neutrophil engraftment was achieved in 87% patients with a median of 19 days. The cumulative incidence of grades II to IV and III to IV acute graft-versus-host disease (GVHD) and chronic GVHD at 1 year were 23%, 3%, and 15%, respectively. No patients developed severe chronic GVHD. Day 100 nonrelapse mortality (NRM) rate was 19.4%. Overall survival, relapse, and disease-free survival rates were 45%, 45%, and 34%, respectively, at 1 year. Subgroup analysis showed that patients who had a history of prior allo-SCT had lower engraftment, higher NRM, and lower overall survival than those not receiving a prior allo-SCT. Our results suggest that PTCy-haploPBSCT after busulfan-containing reduced-intensity conditioning achieved low incidences of acute and chronic GVHD and NRM and stable donor engraftment and low NRM, particularly in patients without a history of prior allo-SCT.

Key Points• HDCA plus CY/TBI improved overall survival relative to CY/TBI in CBT for myeloid malignancy.• HDCA suppressed relapse but did not increase the incidence of severe adverse events or nonrelapse mortality.Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/ CY/TBI (n 5 617) and CY/TBI (n 5 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; highrisk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/ TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m 2 ) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration. (Blood. 2015;126(3):415-422)

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

We retrospectively evaluated the outcomes of 37 adult patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) conditioned with medium-dose VP-16 (VP, 30 mg/kg), cyclophosphamide (CY, 120 mg/kg), and fractionated total-body irradiation (TBI, 12 Gy) (medium-dose VP/CY/TBI). The median age of the patients was 26 years. Thirteen patients underwent transplantation from HLA-matched related donors (MRD), 18 patients underwent transplantation from HLA-matched unrelated donors (MUD), and 6 patients underwent transplantation from HLA-mismatched donors (MMD). Thirty-two patients received bone marrow and 4 patients received peripheral blood stem cells. Ten patients were Philadelphia chromosome-positive (Ph(+)) and 35 patients were in complete remission (CR) at transplantation. All of the patients achieved engraftment, and grade 3 organ toxicity before engraftment occurred in 27 patients. Grade II-III acute graft-versus-host disease (GVHD) and chronic GVHD (cGVHD) occurred in 15 and 18 patients, respectively. No patient developed grade IV acute GVHD (aGVHD) or died of GVHD. At median follow-up of 35.1 months, 32 patients were alive and all Ph(+) patients were alive. Three patients died of relapse and 2 died of transplant-related mortality (TRM). The actuarial 3-year overall survival (OS) rate, relapse rate, and TRM rate were 89.2%, 8.1%, and 5.4%, respectively. Non-CR at transplantation, MRD, and no aGVHD were significant adverse prognostic factors for survival. Medium-dose VP/CY/TBI for adult ALL patients was associated with lower relapse rate and no increase in toxicity, resulting in better survival.